Background

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder that occurs when muscle and supportive tissues of the body, such as the tendons, ligaments, and cartilage, are gradually replaced with bone. As a result, movement becomes limited in the affected areas of the body, usually starting with the neck and shoulders and progressing down the body. Commonly affected areas include the neck, spine, chest, shoulders, elbows, wrists, hips, knees, ankles, and jaw.

Although symptoms do not typically develop until a child is a few months or years old, the disorder may be indicated at birth by the presence of malformed big toes. The big toes may be short and abnormally turned outward in a position called a valgus deviation. This abnormality helps distinguish FOP from other types of bone and muscle disorders. People with FOP may also have short limbs and other bone abnormalities.

There are many complications associated with FOP. The condition leads to progressive loss of mobility as more and more tissues become affected. For example, if extra bone develops in the jaw joints, a person may have difficulty talking or eating. If extra bone develops in the tissues over the rib cage, people may have difficulty breathing. The rates at which new bone forms and the disease progresses vary among patients.

People with FOP may experience a flare-up, or a sudden worsening of symptoms, if they experience any trauma to the muscles or connective tissues. For instance, if a person with FOP falls down, it may trigger episodes of muscle swelling (called myositis), followed by rapid development of bone (ossification) in the injured area. Illnesses, such as the flu, may also trigger flare-ups.

Researchers estimate that FOP affects one out of two million people worldwide.

The life expectancy for patients with FOP is generally poor because there is no cure for the disorder. Most patients die before age 40.

Risk Factors

Nearly all cases of fibrodysplasia ossificans progressiva (FOP) occur randomly with no family history of the disorder. Although, it is possible for people who have the disorder to pass the condition to their children, it is rarely inherited because most people with FOP are unable to have children.

Causes

Genetic mutation: People with fibrodysplasia ossificans progressiva (FOP) are born with mutations in the activin A receptor, type I (ACVR1) gene. Normally, this gene provides the body with instructions on how to produce the activin receptor type I protein, which is a member of a protein family called bone morphogenetic protein (BMP) type I receptors. The ACVR1 protein is present in many body tissues, including the skeletal muscles and cartilage. The protein helps regulate the growth and development of muscles and bones. It also helps control the gradual replacement of cartilage by bone that occurs when a person grows into an adult.

When there is a mutation in the ACVR1 gene, researchers believe that it causes too much bone to grow, resulting in the signs and symptoms of FOP.

Random occurrence: Nearly all cases of FOP occur randomly and are not inherited. Instead, the genetic mutation randomly occurs during the development of the egg, sperm, or embryo.

Inheritance: When FOP is inherited, it is passed down as an autosomal dominant trait. This means that one copy of the mutated gene (from just one parent) is enough for a child to develop the disorder. However, FOP is rarely inherited because most people with the disorder are unable to have children.

Signs and Symptoms

General: Since FOP is a progressive disease, it typically becomes more severe and affects more areas of the body as time goes on. However, disease progression and the rate at which new bone forms vary among patients.

Malformed big toes: People with fibrodysplasia ossificans progressiva (FOP) are typically born with malformed toes. The big toe is typically shorter than normal and abnormally turned outward in a position called a valgus deviation.

Excessive bone growth: During early childhood, most people with FOP develop painful tumor-like swellings (called fibrous nodules) that are visible on the neck, shoulders, and back. These nodules eventually transform into bone in a process called heterotopic ossification. Over time, bone starts to replace the body's muscles and connective tissues along the trunk and limbs of the body.

When the body starts to generate new bone, the patient typically experiences a painful flare-up, or sudden worsening of symptoms, that causes tissue swelling and joint stiffness. During this process, calcium phosphate builds up in the intramuscular tissue. Bone forms once this material transforms into hydroxyapatite crystals. Some people may also experience low-grade fevers. This is because fevers are part of an inflammatory reaction. Flare-ups may last as long as 6-8 weeks.

Flare-ups typically develop after a person experiences trauma to the body, such as a fall. Illnesses, such as the flu, may also trigger flare-ups. However, flare-ups may develop without any known trigger.

Most FOP patients are bedridden by the time they reach their 30s, and they usually die before age 40.

Diagnosis

In most cases, an accurate diagnosis of fibrodysplasia ossificans progressiva (FOP) can be made based on the patient's characteristic signs and symptoms of the disorder. Young children typically have malformed big toes and painful, tumor-like swellings on the head, neck, and/or back.

However, researchers believe that FOP is often misdiagnosed because it is a rare disease, affecting about one out of two million people worldwide. Cancer, aggressive juvenile fibromatosis, and progressive osseous heteroplasia are three of the most common misdiagnoses. Experts estimate that the rate of misdiagnosis of FOP may be 80% or higher.

Complications

General: There are many complications associated with fibrodysplasia ossificans progressiva (FOP) because the condition leads to progressive loss of mobility as more and more parts of the body become affected. Frequent illnesses or trauma to the body may speed up the disease progression. Complications vary among patients with FOP, depending on which part of the body is affected.

Breathing problems: If extra bone replaces the tissues over the rib cage, people may not be able to expand their lungs normally. As a result, breathing may be difficult.

Difficulty speaking or eating: If extra bone develops in the jaw joints, a person may have difficulty speaking or eating. In some cases, difficulty eating may lead to malnutrition.

Limited mobility: As bone replaces muscles and connective tissues, people typically experience limited mobility in the affected parts of their bodies. As a result, everyday activities, such as walking and getting dressed, may be challenging. Most FOP patients are bedridden by the time they reach 30 years of age.

Skin sores: People with FOP, especially adults, often develop pressure sores on their skin. Sore and broken skin may develop if extra bone puts pressure on the skin. Therefore, people with FOP should wear protective padding over bony bumps on their bodies and they are encouraged to change sitting positions frequently. People who sit for many hours during the day are encouraged to use well-padded seat cushions.

Skin sores may also develop if the skin becomes moist or sweaty in difficult-to-reach areas. Because people with FOP often have limited mobility of their joints, they may be unable to properly clean the skin. As a result, bacterial or fungal infections may develop on the skin.

Treatment

General: Currently, there is no known cure or effective treatment for fibrodysplasia ossificans progressiva (FOP). Surgery is not performed to remove extra bone because the trauma of invasive surgery generally leads to the growth of even more bone. Treatment and lifestyle changes may help reduce symptoms, decrease the risk of flare-ups, and prevent complications of FOP.

Minimize the risk of traumatic injuries: People with FOP should take steps to avoid physical injuries because they may trigger flare-ups of the condition. Because people with FOP may have limited mobility and/or difficulty walking, they should move things that they may trip over, such as shoes, clothes, and books. Removing throw rugs or applying double-sided tape to the bottom of such rugs may help prevent them from sliding. Wearing rubber-soled slippers that do not slip is also recommended. Patients should keep most or all of their items in locations that do not require the use of a step stool. Grab bars can be installed in the shower and near the toilet. A non-slip bath mat in the shower or tub may help reduce the risk of injury. Proper lighting inside the home and handrails on the staircases are important. If there are steps to the front door, a ramp may help reduce the risk of falls.

Assisted mobility devices: Some people may require assisted mobility devices to help them walk. This may include a cane, walker, wheelchair, or mobilized chair. Individuals should talk to their healthcare providers to determine the best options.

Recommended physical activities: People with FOP should not stretch the joints or soft tissues of the body because doing so may trigger flare-ups. Rigorous movements should also be avoided. This includes activities that have a high risk of injury or falling, such as running, bicycling, or contact sports. Because people with FOP have limited mobility, they are more likely to fall than healthy individuals and injuries may cause flare-ups.

However, active range of motion of a joint should be encouraged as long as it is comfortable for the patient. Low-intensity and low-impact exercise is important to maintain muscle strength and cardiovascular health. Experts often recommend swimming for people with FOP. Warm water may also help reduce pain, relax muscles, and increase blood flow.

Types of clothing to avoid: People with FOP should avoid wearing tight clothing, hard buckles or buttons, tight elastics, straps, or body braces (i.e. to improve posture), tight shoes or shoe laces, or any item that puts prolonged pressure on the body. Such items may increase the risk of flare-ups.

Good oral hygiene: If extra bone develops in the jaw joints, a person may have difficulty speaking or eating. Therefore, preventive care of the jaw and mouth is especially important. If individuals practice good hygiene, they are less likely to need dental procedures, which can trigger flare-ups of FOP.

People should brush their teeth twice a day with fluoride toothpaste. The tongue should also be brushed to help remove dead cells and odor-causing bacteria. Toothbrushes should be replaced every two to three months. A floss or interdental cleaner should be used once a day to remove plaque and food particles between the teeth. Dentures should be removed at night and thoroughly cleaned before they are placed into the mouth in the morning. Individuals should visit their dentists every six months for routine cleanings and checkups.

Avoid unnecessary intramuscular injections: Injections into the muscle are considered dangerous for FOP patients because they may trigger bone formation at the injection site. Immunizations and local anesthetics are two types of shots that are given intramuscularly. Once a person is diagnosed with FOP, intramuscular injections should be avoided. Most children have already received the standard childhood immunizations before they are diagnosed with FOP and they may experience bone growth at the injection site. Injections that are given underneath the skin are generally considered safe for people with FOP. Patients should talk to their doctors to determine the safest and most effective alternatives to intramuscular injections.

Nonsteroidal anti-inflammatory drugs (NSAIDs): Nonsteroidal anti-inflammatory drugs (NSAIDs) may help reduce pain and inflammation during a flare-up of FOP. However, these drugs do not cure or stop the progression of FOP. Commonly used over-the-counter NSAIDs include ibuprofen (Advil® or Motrin®) and naproxen sodium (Aleve®). Higher doses of these drugs are also available by prescription. Commonly prescribed NSAIDs include diclofenac (Cataflam® or Voltaren®), nabumetone (Relafen®), and ketoprofen (Orudis®). NSAIDs may be taken by mouth, injected into a vein, or applied to the skin. These medications are generally taken long-term to manage symptoms.

The frequency and severity of side effects vary. The most common side effects include nausea, vomiting, diarrhea, constipation, decreased appetite, rash, dizziness, headache, and drowsiness. The most serious side effects include kidney failure, liver failure, ulcers, heart-related problems, and prolonged bleeding after an injury or surgery. About 15% of patients who receive long-term NSAID treatment develop ulcers in the stomach or duodenum.

Accutane®: It has been suggested that isotretinoin (Accutane®), a medication commonly used to treat acne, may help prevent the connective tissues of FOP patients from being replaced with bone. This drug is dangerous for pregnant women to take because it can interfere with the normal formation of the skeleton in the embryo. For this reason, however, Accutane® has been suggested as a possible treatment for FOP. This is because the bone growth in FOP patients is similar to the way bone grows in the fetus. Because there is very limited research in this area, it remains unknown if Accutane® is safe and effective for patients with FOP.

Accutane® may cause side effects, including dry mouth, dry nose, hair loss, vision loss, and increased triglyceride levels in the blood. There is also some concern that this medication may stimulate the growth of bone that has already formed.

Future drugs and treatments: The safety and effectiveness of a new drug that might help control excessive bone growth caused by FOP has been researched.

Integrative Therapies

Currently, there is a lack of scientific data on the use of integrative therapies for the treatment or prevention of fibrodysplasia ossificans progressiva (FOP).

Prevention

General: There is currently no known method of prevention for fibrodysplasia ossificans progressiva (FOP). Most cases occur randomly and are not passed down among families. Below are some ways to help prevent flare-ups and reduce the risk of FOP complications.

Avoid unnecessary intramuscular injections: Injections into the muscle are considered dangerous for FOP patients because they may trigger a flare-up and bone formation at the injection site. Immunizations and local anesthetics are two types of shots that are given intramuscularly. Once a person is diagnosed with FOP, intramuscular injections should be avoided. Most children have already received the standard childhood immunizations before they are diagnosed with FOP. Injections that are given underneath the skin are generally considered safe for people with FOP.

Good oral hygiene: If extra bone develops in the jaw joints, a person may have difficulty speaking or eating. Therefore, preventative care of the jaw and mouth is especially important. If individuals practice good hygiene, they are less likely to need dental procedures, which can trigger flare-ups of FOP.

People should brush their teeth twice a day with fluoride toothpaste. The tongue should also be brushed to help remove dead cells and odor-causing bacteria. Toothbrushes should be replaced every two to three months. A floss or interdental cleaner should be used once a day to remove plaque and food particles between the teeth. Dentures should be removed at night, and thoroughly cleaned before they are placed into the mouth in the morning. Individuals should visit their dentists every six months for routine cleanings and checkups.

Minimize the risk of traumatic injuries: People with FOP should take steps to avoid physical injuries because they may trigger flare-ups of the condition. Because people may have limited mobility and/or difficulty walking, patients should move things that they may trip over, such as shoes, clothes, and books. Removing throw rugs or applying double-sided tape to the bottom of such rugs may help prevent them from sliding. Wearing rubber-soled slippers that do not slip is also recommended. Patients should keep most or all of their items in areas that do not require the use of a step stool. Grab bars can be installed in the shower and near the toilet. A non-slip bath mat in the shower or tub may help reduce the risk of injury. Proper lighting inside the home and handrails on the staircases are important. If there are steps to the front door, a ramp may help reduce the risk of falls.

Some people may require assisted mobility devices to help them walk. This may include a cane, walker, wheelchair, or mobilized chair. Individuals should talk to their healthcare providers to determine the best options for them.

Recommended physical activities: People with FOP should not stretch the joints or soft tissues of the body, such as the tendons, ligaments, or cartilage, because doing so may trigger flare-ups. Rigorous movements should also be avoided. This includes activities that have a high risk of injury or falling, such as running, bicycling, or contact sports. Because people with FOP have limited mobility, they are more likely to fall than healthy individuals and injuries may cause flare-ups.

However, active range of motion of a joint should be encouraged as long as it is comfortable for the patient. Low-intensity and low-impact exercise is important to maintain muscle strength and cardiovascular health. Experts often recommend swimming for people with FOP. The warm water may also help improve symptoms of a flare-up.

Types of clothing to avoid: People with FOP should avoid wearing tight clothing, hard buckles or buttons, tight elastics, straps, or body braces (i.e. to improve posture), tight shoes or shoe laces, or any item that puts prolonged pressure on the body. Such items may increase the risk of experiencing a flare-up.

Author Information

This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography

Natural Standard developed the above evidence-based information based on a thorough systematic review of the available scientific articles. For comprehensive information about alternative and complementary therapies on the professional level, go to www.naturalstandard.com. Selected references are listed below.

The information in this monograph is intended for informational purposes only, and is meant to help users better understand health concerns. Information is based on review of scientific research data, historical practice patterns, and clinical experience. This information should not be interpreted as specific medical advice. Users should consult with a qualified healthcare provider for specific questions regarding therapies, diagnosis and/or health conditions, prior to making therapeutic decisions.